Structural basis for dimerization quality control

Abstract

Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration 1 . Dimerization quality control (DQC) further improves proteostasis by eliminating complexes of aberrant composition 2 , yet how it detects incorrect subunits is still unknown. Here, we provide structural insight into target selection by SCF FBXL17 , a DQC E3 ligase that ubiquitylates and helps degrade inactive heterodimers of BTB proteins, while sparing functional homodimers. We find that SCF FBXL17 disrupts aberrant BTB dimers that fail to stabilize an intermolecular β-sheet around a highly divergent β-strand of the BTB domain. Complex dissociation allows SCF FBXL17 to wrap around a single BTB domain for robust ubiquitylation. SCF FBXL17 therefore probes both shape and complementarity of BTB domains, a mechanism that is well suited to establish quality control of complex composition for recurrent interaction modules.

Identification of an atypical interaction site in the BTB domain of the MYC-interacting zinc-finger protein 1

“…This versatility is thought to be facilitated by the high surface variability of BTB domains, despite their overall conserved architecture, and by varied extensions to their core that generate distinct binding sites. BTB domains in the BTB-ZF, BTB-kelch, and MATH-BTB protein families comprise N-terminal extensions (b1 and/or a1) that drive their dimerization or higher-order self-association (Stogios et al, 2005) and regulate their stability in the cell (Mena et al, 2018(Mena et al, , 2020. MATH-BTB-type proteins, such as SPOP, include an additional C-terminal, a-helical extension that serves as a substrate adaptor in cullin-RING-type ubiquitin ligase (CRL) complexes (Zhuang et al, 2009).…”

“…Another difference between MIZ1-and BCL6-type BTB domains lies in the absence of a b1 strand and the associated lower b sheet in MIZ1 (Figures 6A and 6B). Interestingly, the conformational dynamics of the b1 strand are critical for the stability-based selection of BTB homodimers in the context of CRL-mediated dimerization quality control (Mena et al, 2018(Mena et al, , 2020.…”

“…More broadly, our findings illustrate an additional facet of the structural versatility of the BTB fold that may allow for functional discrimination between homo-and heterodimers of MIZ1 in the cell. This adds to the structurally distinct concept of dimerization quality control, which explains the selective destabilization of BTB heterodimers by the RING-type ligase SCF-FBXL17 (Mena et al, 2018(Mena et al, , 2020.…”

Ubiquitin‐dependent regulation of transcription in development and disease

“…BCL6, however, also forms aberrant heterodimers that are unable to engage co‐repressors and impede gene regulation (Mena et al, 2018). A protective pathway referred to as dimerization quality control selectively detects and eliminates the inactive heterodimers to ensure proper BCL6 complex formation (Mena et al, 2018; Mena et al, 2020).…”

An E3 ligase guide to the galaxy of small-molecule-induced protein degradation

“…Some substrates possess several copies of a degron to allow for multivalent and high-affinity recognition (Csizmok et al, 2017;Tang et al, 2007;Werner et al, 2018). While short linear motifs have been studied most extensively, structural degrons also exist: providing a recent example, SCF FBXL17 recognizes the shape, rather than the sequence, of its target broad-complex, tramtrack, and bric-à -brac (BTB) domain (Mena et al, 2018(Mena et al, , 2020. Finally, some E3 ligases function predominantly by extending ubiquitin chains and thus recognize ubiquitin itself as their substrate (Eddins et al, 2006;Koegl et al, 1999;Wickliffe et al, 2011;Yau et al, 2017).…”